Dehalogenation of steroids



Patented May 1, 1945 DEHALOGENATION or s'rnaoms Percy L. Julian, Maywood, John Wayne Cole, Chicago, Arthur Magnani, Wilmette, and Harold E. Conde, Chicago, 111., asslgnors to The Glidden Company, Cleveland, Ohio, a corporation of Ohio No Drawing.

Claims.

This invention relates to the removal of halogen from halogenated compounds of the cyclopentano-polyhydrophenanthrene series, and particularly from 3-keto-5,6-dihalo-compounds.

The classical method of removing halogen from dihalides by means of zinc and acetic acid,.when applied to 5,6-dihalo-3-keto-steroids, gives the unsaturated ketone in relatively poor yields and contaminated with impurities which are frequently difficult or impossible to remove. Steroids containing sensitive functional groups such as carbonyl or alcoholc groupings may suffer reduction of these functional groups resulting in the formation of hydrocarbons, pinacols and the like. Thus Butenandt, Ber. 67, 2087 (1934) on debmmination of 5,6-dibromo-pregnandione-3,20,

Application February 10, 1944, Serial No. 521,850 Y ess for the dehalogenation of 3-keto-5,6 dihalo compounds of the steroid series at room temperv atures.

found in certain instances that ring A had suffered complete reduction of its carbonyl group to a methylene group. Fernholz had difliculty in the isolation of crystalline progesterone, Ber. 67, 2027 (1934) following this debromination procedure. Steiger and Reichstein, Helv. Chim. Acta 20, 1177 (1937) had similar difficulty in isolating pure desoxycorticosterone acetate following asimilar debromination procedure.

An alternative method for removal of halogen is the treatment of a dihalide with sodium iodide, which procedure gives good results in certain casessee Schoenhaimer, J. Biol. Chem. 110, 461 (1935). This reaction is an equilibrium reaction and at ordinary temperatures goes very slowly in the desired direction. In cases where the dihalo compound can be treated with sodium iodide at elevated temperatures, such aswas the case with Schoenheimers cholesterone dibromide, the reaction proceeds with good yield. Most 3-keto- 5,6-dihalo-steroids are, however, sensitive to heat,

and the reaction with sodium iodide must be car-' At these ried out at relatively low temperatures. temperatures it is difiicult to remove {all halogen within a reasonable time and frequently the unsaturated S-keto-derivative is found to contain traces of halogen, which is fatal to the stability of most 3-keto-A -steroids. For example, a crystalline progesterone preparation containing a An additional object is to provide a process for dehalogenating of 3-keto-5,6, dihalo compounds of the steroid series whereby increased yields of the resulting unsaturated compounds are obtained.

A further object is to provide an efllcient proc- Other objectswill be apparent to those skilled in the art from the following description.

We have found that the halogen is removed rapidly and cleanly from the dihalo-ketones by means'of chromous chloride, vanadous chloride or titanous chloride at room temperature. The A -3-keto-steroid isin some cases crystallized directly from the mixture; in other cases it is extracted by means of a water-immiscible solvent then concentrated. In all cases the product, without further purification, has been of a relatively high degree of purity.

While our method of dehalogenation has been developed primarily for the preparation of M43- keto steroids, we have observed also that chromous chloride and the other chlorides mentioned above will dehalogenate other dihalides.

The following examples illustrate the invention: i EXAMPLE I To a suspension of 30 grams of finely powdered 3-hydroxy-A -ter-nor-cholenyl-diphenyl-carbinol (recrystallized from chloroform) in 250 cc. glacial acetic acid is added at room temperature a solution of 2.7 cc. (8.4) grams of bromine in 150 cc. of glacial acetic acid. The solution is warmed to 96-100 F. and an ozone-oxygen mixture containing 3 to 4% of ozone by volume passed in for 30 minutes at a rate of flow of 3.5 liters per minute. The dibromide of the carbinol-usually crystallizes out of solution toward the end of the bromination time and the solution should be clear at the end of the ozonization. During the ozonization the temperature rises several degrees.

The solution after ozonization is cooled at once to F. and the oxidizing mixture, cooled before using, and consisting of 10 grams 'chromic oxide, 1 cc. concentrated sulfuric acid, 15 cc. of water and cc. of glacial acetic acid, is added with stirring during several minutes, never allowing the temperature of the reaction mixture to rise above 80 F. After standing for 1 hour at room temperature, 20 cc. of methanol is added to the reaction mixture. The reaction mixture is now diluted with 500 cc. of glacial acetic acid and the resulting solution cooled to 60 F. 300 cc. of one molar chromous chloride solution, prepared according to the procedure of Conant and Cutter J. A. C. S. 48 1023 (1926), is thenadded with shaking under an atmosphere of carbon dioxide. After standing for hour (or the solution may stand as long as over-night if desired), the solution is concentrated under the vacuum of a water pump and at 80 to 90 C. until 500 to 600 cc. of distillate have,

- tilled. The residue from the steam distillation is cooled, taken up in ether and the ether extract again washed successively with water, dilute sodium hydroxide and water. The final ether solution is concentrated to a volume of about 20 cc. whereupon progesterone crystallizes out on cool-' ing. The crude progesterone is filtered and washed with a cold petroleum ether mixture. The average yield is about 7.5 grams, M. P. 118 to 127 C. On again steam distilling, the mother liquors and working up as indicated above, 2 grams of a second crop of material, M. P. 116 to 121 may be obtained. The crude progesterone is purified by crystallization from acetone. yielding colorless prisms melting at 127 to 129 C.

EXAIVIPLE II The procedure was identical with that in Example I except that the chromous chloride was replaced by 300 cc. of a 1 molar solution of vanadous chloride prepared according to the methd of Conant and Cutter, J. A. C. S. 48 1023 (1926),

and the vanadous chloride was added to the mixture without dilution of the mixture prior to the addition of the debrominating agent. The crude progesterone had a melting point of 117. to 124 C.

EXAMPLE III The procedure was the same as in Example I except that 300 cc. of a commercial 20% solution of titanous chloride was used as the debrominating agent, and there was no dilution of the reaction mixture prior to the addition of the debrominating agent. The crude progesterone had a melting point of 117 to 124 C.

EXAMPLEIV The procedure was the same as in Example III, except that the reaction mixture was heated on a steam cone for one hour for the debromination. The crude progesterone had a melting point of 113 to 119 C;

EXAMPLE V Paocasrnaona FROM PROGESTERONE msaowna stance melting at about 235, then 1.7 grams (92% of the theoretical amount) of colorless crystalline progesterone.

Similarly the acetic acid solution of crude 5,6- dibromo-pre'gnan-3,20-dione prepared from 2.0 rams of pregnen-3-ol-20-one was treated with I 60 cc. of chromous chloride solution under car- EXAMPLE VI Daaaomm'non on annaosrananrona manor/[ma The dehydroandrosterone dibromide, obtained by brominating 2.0 grams of dehydroandrosterone, M. P. 135-140, in chloroform then removing the solvent, was dissolved in acetic acid and oxidized with'1.2 grams of chromic acid for 2 hours at 26 C. The androstenedione dibromide was separated by means oi? ether, washed, concentrated, then treated in acetone solution under carbon dioxide with 60 cc. of one-molar chromous chloride solution for two hours. A part 01' the acetone was distilled, and the residue diluted and extracted with ether. The washed ether extract yielded 1.6 grams of colorless A '-androsten-3,17- dione melting at 167-169.

In a comparative androstenedione preparation employing zinc dust and acetic'acid as the debrominating method, 2 grams of dehydroandrosterone-brominated and oxidized exactly as aboveyielded 1.0 grams of androstenedione melting at 152-155, plus gummy material from the mother liquor.

EXAMPLE VII .PREPARATION or A -3- xr'ro BISNORCHOLENIC ACID A suspension of grams of A -3-hydroxybisnorcholenic acid, M. P. 288490, in 300 cc. of glacial acetic acid at 25 C. was treated with 4.1 grams of bromine in cc. of acetic acid. The resulting clear solution was oxidized for two hours with 4 grams of CrOa in 8 cc. of water and 30 cc.

of acetic acid. 10 cc. of methanol was addedto destroy excess CrOs, and the resulting ,solution of dibromo-keto acid was mixed, under carbon dioxide, with 150 cc. of chromous chloride solution and held at C. for two hours. A part of the acetic acid was removed by distillation. A part of the product, A -3-keto-bisnorcholenic acid melting at 269-271, crystallized directly from the concentrate, but a considerable portion was also extracted from the mother liquor with ether. The yield of first crop colorless crystals was 6.0

grams.

EXAMPLE VIII PREPARATION or A -3-xa'ro arrocnoramc son) A suspension of 4.7 grams of. A"--3-hydroxy-.

etio-cholenic acid M. P. 276-278, in 220 cc. of glacial acetic acid at25 C. was treated successively with 2.2 grams of bromine in 22 cc. of acetic acid during five minutes, with 2.0 grams otcin-omium trioxide in 4, cc. of water and cc. of acetic acid for two hours, with 10 cc. of methanol for 20 minutes, then with 100 cc. of one-molar chromous chloride solution under carbon dioxide for two hours. From the resultin green lution crystals of the product... P {i-keto-etiocholenic acid, began to separate. :Slow' addition of 250 cc. of water broughtdown affir'st crop or 3.8 grams of the theoretical'amount) 0f colorless crystals of the keto acid melting' at 244. Ether extraction of themother liquor gave a small additional quantity of the keto acid.

Pnanrurrron or nasoxwcoarrcosmom ACITATI A chloroform solution of 1.5 grams of A"- pregnen-3,21-dio1-20 one 21 monoacetate was treated with 0.65 gram of bromine dissolved in chloroform. The solvent was removed, the dibromide dissolved in acetic acid and oxidized for one hour at 25 C. with 0.7 gram of (H03. The 5,8-dibromo-3-ketone so obtained was separated by dissolving it in ether and washing thoroughly with water. The ether solution was concentrated to about 00., then diluted with 90 cc. of acetone, covered with carbon dioxide to exclude air, then treated with 50 cc. of one-molar chromous chloride solution at 28 C. After two hours the acetone was partly removed by distillation, and the unsaturated ketone extracted from the residue by means of ether. Upon evaporating the ether 1.2 grams of colorless crystals ot'desoxycorticosterone acetate (melting at 158) separated.

EXAMPLE X PREPARATION or I'I-METHYL-TESTOSTERONB A. A -1 7 -methyl-trans-androstene-3,1 7 -di0l gm. dehydroandrosterone in 1500 cc. absolute ether.

13.4 gm. magnesium, 80 gm. methyl iodide in 300 cc. absolute ether.

The Grignard solution was prepared in a 3-liter, S-necked round-bottom flask fitted with a reflux condenser and a mercury seal stirrer. The ether solution of dehydroandrosterone was added portionwise to the Grignard solution as rapidly as possible from a separatory funnel. The white. ether-insoluble Grignard product came out oi! solution immediately. The whole was then warmed on a steam bath with continued stirring overnight, maintaining the steam flow at a rate such as to keep the ether gently boiling. The whole mixture was then poured onto ice-and and ammonium chloride with vigorous agitation. The ether-insoluble portion 01' the product was illtered oil and washed well with water and ether. dried and weighed. The ether portion of the illtrate was washed well with water and concentrated for crystallization of a second crop.

First crop of product= 15.0 gm., M. P. 200-202 C. Second crop of product= 2.0 gm., M. P. 200-201" 0.

B. 17-methul-testosterone stirring at a temperature of 60" F. and the mix-' ture then allowed to stand overnight at a temperature of 60-70 F. 10 cc. methanol were added and the solution diluted with an equal volume of acetic acid. The solution was then cooled to 60 F. and 85 cc. (2 moi. excess) of 1 M chromous chloride solution was added. with shaking under an atmosphere oi carbon dioxide. This mixture was then allowed to stand for 1 /2 hours, after which it was concentrated under vacuum produced by a water pump to approximately V; volume, diluted to three liters with cold water and extracted with ether. The clear, water-white etherv extract was washed with water, dilute sodium hydroxide solution and finally with water, dried over sodium sulfate and concentrated to a syrup. On scratching with a seed of methyltestosterone, crystallization of the product began. The mixture was diluted with ether-petroleum ether, and set in the ice box for crystallization. The first crop was filtered and washed with petroleum ether. was obtained by concentration of the mother liquor. I

lst crop=2..0 gm., M. P. 2nd crop=0.5 gm, M. P.

The M. P. may be raised by recrystallization.

Reference is made to copending application Serial No. 521,851, filed concurrently herewith.

Having described the invention, what is claimed 1. The method oi dehalogenating halides of the'steroid series containing halide groups attached to adjacent carbon atoms which comprises treatment oi said steroid with a halide salt selected from the class consisting of chromous chloride, vanadous chloride and titanous chloride as the dehalogenating agent.

2. The method of removing halogen from 5,6- dihalo 3-keto steroids which comprises removing said halogen with a halide salt selected from the class consisting of chromous chloride, vanadous chloride, and titanous chloride as the dehaiogenatlng agent.

3. The method of removing bromine from 5,6- dibromo-3-keto steroids which comprises removing a halide salt selectell from the class consisting of chromous chloride, vanadous chloride, and titanous chloride, as the debrominating agent.

4. The method of removing halogen from 6.6- dihalo-3-keto steroids which comprises removing halogen from said steroids with the aid of chromous chloride as a dehalogenating agent.

5. The method of removing bromine from 5,6- dibromo-Ii-keto steroids which comprises removing bromine from said steroids with the aid of chromous chloride as a dehalogenating agent.

6. The method of debrominating 5,6-dibromo- 3-keto steroids oi the pregnane series which comprises removing bromine from said steroids with t e aid of a halide salt selected from the class consisting of chromous chloride, vanadous chloride, and titanous chloride as debrominating a ents.

'1. The method or removing bromine from progesterone dibromide which comprises removin PERCY L. JULIAN. JOHN WAYNE COLE. ARTHUR MAGNANI. HAROLD E. CONDE.

A second crop bromine from said steroid with the aid of 

